Major objectives of this research are to gain a better understanding of positive and negative mediators of inflammation induced intestinal fibrosis, an incurable complication of Crohn's disease (CD). Findings in animal models of acute colitis and in patients with CD indicate benefits of growth hormone (GH) therapy in CD but the documented fibrogenic effects of GH and insulin-like growth factor-I (IGF-I) which is induced by GH, support a hypothesis that GH therapy may exacerbate fibrosis in CD. Locally expressed IGF-I is up-regulated in myofibroblasts at sites fibrosis in CD and animal models of chronic intestinal inflammation implicating IGF-I as an endogenous mediator of fibrosis. Preliminary data support a hypothesis that suppressors of cytokine signaling (SOCS), may limit the fibrogenic actions of therapeutic or endogenous cytokines and growth factors in the inflamed intestine. Other data support a hypothesis that IGF-I interacts with another key cytokine, TNF-alpha to mediate collagen synthesis or proliferation in intestinal myofibroblasts, key cellular mediators of fibrosis in CD. Specific aims are as follows:Aim 1 will define if systemic GH increases fibrosis, circulating or locally expressed IGF-I during PG-PS induced enterocolitis. Cellular sites and levels of SOCS expression will be assessed to verify that SOCS2 or SOCS3 are expressed at in vivo sites that would permit them to limit fibrosis.Aim 2 will define if IGF-I mediates GH action on collagen synthesis or proliferation in intestinal myofibroblasts and test whether SOCS limit GH or IGF-I action.Aim 3 will define if mice with absolute or mesenchyme-specific SOCS2 deficiency show altered fibrosis, JGF-I induction or GH action during TNBS-colitis.Aim 4 will define mechanisms if TNF-alpha has additive or synergistic effects with IGF-I, to induce collagen synthesis in intestinal myofibroblasts and if SOCS limit these effects.